GENERIC DRUG REGISTRATION AND REGULATORY …

www.wjpr.net Vol 7, Issue 16, 2018. 800

Peddi et al. World Journal of Pharmaceutical Research

GENERIC DRUG REGISTRATION AND REGULATORY

REQUIREMENTS IN EUROPEAN COUNTRIES

Meghana Peddi*, M. V. Nagabhushanam, D. Nagarjuna Reddy, Brahmaiah

Bonthagarala and G. Ramakrishna

Department of Pharmaceutical Management and Regulatory Affairs, Hindu College of

Pharmacy, Amaravathi Road, Guntur, Andhra Pradesh, India-522002.

ABSTRACT

The aim of this document is to examine methodological challenges by

comparing generic drug registration and regulatory requirements in

European countries. European countries are fast growing and emerging

markets in pharmaceutical sector. Increasing patent expirations and the

need for less expensive drugs is fuelling the growth of generics market

in the region. However, there are some challenges to be met in order to

sustain the growth. Hence the objective of present study is to analyse

overall aspects like the requirements for registration of generics in the

following 28 “EMA” (European medicines agency) countries, Drug

registration procedure for the approval of generic drug in these

countries, Mark out the differences in the requirements to register

generic drug product in these countries. The primary purpose of the

rules governing generic drugs in Europe is to safeguard to public

health. It is the role of public regulatory authorities to ensure that

pharmaceutical companies comply with regulations. There are legislations that require drugs

to be developed, tested, trailed, and manufactured in accordance to the guidelines so that they

are safe and patient’s well - being is protected. The regulatory submissions in the EU, in the

world continue to have significant differences. When compared to others the EU approval

process is typical and contain more data to be summarized for the dossier submission.

KEYWORDS: Generic drug registration, Regulatory requirements, European medicines

agency (EMA), European countries.

World Journal of Pharmaceutical Research SJIF Impact Factor 8.074

Volume 7, Issue 16, 800-815. Research Article ISSN 2277– 7105

Article Received on

22 June 2018,

Revised on 12 July 2018,

Accepted on 02 August 2018,

DOI: 10.20959/wjpr201816-13108

*Corresponding Author

Meghana Peddi

Department of

Pharmaceutical

Management and

Regulatory Affairs, Hindu

College of Pharmacy,

Amaravathi Road, Guntur,

Andhra Pradesh, India-

522002.



1. INTRODUCTION

GENERIC DRUGS

A generic drug (generic drugs, short: generics) is a drug defined as "a drug product that is

comparable to a brand/reference listed drug product in dosage form, strength, quality and

performance characteristics, and intended use.

Generic drugs are labeled with the name of the manufacturer and the adopted name

(nonproprietary name) of the drug.

A generic drug must contain the same active ingredients as the original formulation. The

generic drug have same rigid standards as the innovator drug.

Contains the same active ingredients as the innovator drug

Be identical in strength, dosage form, and route of administration

Have the same use indications

Be bioequivalence

Current Status of Generics in Europe

Europe, with its fast-growing, young population and uninsured majority represent great

opportunity for generics in the pharmaceutical industry.

Flag of Europe

Generic market shares vary from country to country, presenting differing oppurtunities for

generic manufacturers, see Figure 1, but in general are increasing across the regions.

Increasing use of generics in the region is expected due to healthcare reforms – making drugs

available to more of the population – and governmental cost-containment strategies. The

expanding middle class is also expected to drive demand for medicines, and especially

generics, in the region.



FIGURE 1: Generic market share in Selected European countries (2016).

GENERIC DRUG DEVELOPMENT

Pharmaceutical drug discovery and development has seen tremendous changes over the

recent decades. A recent literature review concluded that medicines are among the most

valuable forms of health care and are instrumental in treating various diseases more

effectively. Generic medicines market shares differ substantially in Europe. Figure 2 provides

an overview of the evolution of the market shares in ten European countries from June 2002

until March 2007. Figure 2(a) shows the evolution in five countries with high generic

medicine market share (Denmark, Germany, the Netherlands, Sweden and UK) while Figure

2(b) shows the evolution in five countries with low generic medicine market share (Austria,

Belgium, France, Italy and Spain). Generic medicine market shares have increased in all ten

countries and this is due to the various political measures taken by governments.

FIGURE 2: Evolution of Higher and Lower Generic Market Share in Five Countries.



INTRODUCTION TO EMA

The European Medicines Evaluation Agency (here after referred to as EMA) is a

decentralised agency of the European Union (EU). The Management Board is the European

Medicines Agency's integral governance body. The Agency is responsible for the scientific

evaluation, supervision and safety monitoring of medicines developed by pharmaceutical

companies for use in the EU. EMA protects public and animal health in 28 EU Member

States, as well as the countries of the European Economic Area, by ensuring that all

medicines available on the EU market are safe, effective and of high quality. EMA serves a

market of over 500 million people living in the EU.

All parties are linked by an IT network EudraNet. (EUDRANET, the European

TelecommunicationNetworkinPharmaceuticals (European Union Drug Regulating Authoritie

s Network), is an IT platform to facilitate the exchange of information between regulatory

partners and industry during submission and evaluation of applications).

Organization chart of the European Medicines Agency

ELECTRONIC COMMON TECHNICAL DOCUMENT (eCTD)

The European countries established the electronic common technical document (eCTD) as

their format for submissions. It is a standard derived from ICH CTD. The eCTD is defined as

an interface for industry to agency transfer of regulatory information while at the same time

http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500017948



taking into consideration the facilitation of the creation, review, lifecycle management and

archival of the electronic submission.

STRUCTURE OF eCTD

Figure 3: Structure of eCTD.

eCTD application

An eCTD application may comprise a number of sequences. In the EU an eCTD application

may comprise several dosage forms and strengths, all under one invented product name.

Some review tools describe such a collection as a dossier.

EGA (European Generic Medicine Association)

The EGA was established in 1993. The EGA is the official representative body of the

European generic and biosimilar pharmaceutical industry, which is at the forefront of

Providing high-quality affordable medicines to millions of Europeans and stimulating

Competitiveness and innovation in the pharmaceutical sector.

Generic Drug Registration in Europe

Registration procedure of drugs in EU

National Procedure

Centralized Procedure

Decentralized Procedure

Mutual Recognition Procedure

Marketing Authorization based on approval received from above procedures

1. Repeat use application



2. Duplicate use application

Dossier requirements for generic drug application in Europe

The requirements for the dossier for the European countries are in principle very similar to

requirements for the ICH countries.

Dossier for generic drug filling shall be submitted in the form of CTD in Europe. Generic

Drugs are approved under MAA (Marketing Authorization Application).

Types of Applications

Generic Application – According to Article 10 (I) of Directive 2001/83/EC, the applicant is

not required to provide the results of Pre clinical tests and Clinical tests if he can demonstrate

that the medicinal product is a generic medicinal product of a reference medicinal product

which is or has been authorized for not less than 8 years in a Member State or a Community.

A medicinal product is defined as a generic medicinal product if it has –

The same qualitative and quantitative composition in active substance as that of reference

product.

The same pharmaceutical form as the reference product.

And whose Bio-equivalence with the reference medicinal product has been Demonstrated

with appropriate Bio-availability studies.

2. SCOPE OF THE STUDY

European countries are fast growing and emerging markets in pharmaceutical sector.

Increasing patent expirations and the need for less expensive drugs is fuelling the growth of

generics market in the region. However, there are some challenges to be met in order to

sustain the growth. Hence the objective of present study is to analyze overall aspects about:

The requirements for registration of generics in the following 28 “EMA” (European

medicines agency) countries.

Drug registration procedure for the approval of generic drug in these countries.

Mark out the differences in the requirements to register genric drug product in these

countries.



3. METHODOLOGY

The dissertation work was done in order to project industrial approach in facilitating

pharmaceutical company’s entry into the market of European countries.

Criteria for selection of study parameters

As the generic drug registration in European countries is a sequential process, four

parameters are selected for the understanding the regulatory registration and requirements

Part 1: Requirement for filing application

Part 2: Documents and study information required for submission

Part 3: Product registration and dossier submission

Part 4: Comparison study

4. RESULTS

Table 1: General Comparsion of Selected European Countries.

S. No. Country Ma

status Validity

Sunset

clause for 3

years

Format

followed

Renewal for

every 5 years

Format

included in

thesis

1 Germany Granted 5 years If granted eCTD Not needed eCTD

2 Poland Granted 5 years If granted eCTD Not needed eCTD

3 Netherlands Granted 5 years If granted eCTD Not needed eCTD

4 Denmark Granted 5 years If granted eCTD Not needed eCTD

5 Sweden Granted 5 years If granted eCTD Not needed eCTD

6 France Granted 5 years If granted eCTD Not needed eCTD

7 Spain Granted 5 years If granted eCTD Not needed eCTD

8 Ireland Granted 5 years If granted eCTD Not needed eCTD

9 Ausrtia Granted 5 years If granted eCTD Not needed eCTD

10 Greece Granted 5 years If granted eCTD Not needed eCTD

Table 2: Generic Drug Dossier Submission in Europe.

Requirements Europe

Agency

Multiple Agencies

EMEA

CHMP

National Health Agencies

Registration Process

Multiple Registration Process

Centralized (Europea Community)

Decentralized (At least 2

member states)

Mutual Recognition (At

least 2 member states)

National (1 member

state)

TSE / BSE Study data TSE / BSE Study data required



Application MAA

Stability data

The stability data for

accelerated studies are

submitted for complete 6

months at the time of original

Submission.

Approval time 12 months

Pharmacopeias BP/Ph. Eur

Process

Validation required

Braille code Braille code is required on labelling

Post

approval changes

Post variation in the approved drug

Type 1A variation

Type 1B variation

Type II variation

Table 3: Administrative Requirements in Europe.

S. No. Requirement Europe

1 Application MAA

2 Debarment classification Not required

3 Number of copies 1

4 Approval Timeline 12 months

5 Fees 10-20 lakhs

6 Presentation eCTD

Table 4: Finished Product Control Requirements in Europe.

S. No. Requirement EU

1 Justification ICH Q6A

2 Assay 95-105%

3 Disintegration Required

4 Color Identification Required

5 Water Content Not required

Table 5: Manufacturing & Control Requirements in Europe.


1 Number of batches 3

2 Packaging Required

3 Process Validation Required

4 Batch Size Minimum of 1,00,000 Units

Table 6: Stability Requirements in Europe.


1 Number of batches 2

2 Condition 25/60 - 40/75

3 Date & Time of Submission 6 Months Accelerate & 6 Months long term

4 Container orientation Do not address

5 Clause Vol 4 EU Guidelines for medicinal products

6 QP Certification Required



Table 7: Bioequivalence Requirements in Europe.


1 CRO Audited by MHRA

2 Reserve Sample No such requirement

3 Fasted / Fed No such requirement

4 Retention of samples No such requirement

Table 8: Documents Comparsion of Selected European Countries.

S. No. Administrative

Documents Germany Poland Denmark Sweden Spain Ireland Greece

1 Application form 2 Audit certificate 3 Import licence 4 Power of attorney 5 Testing site 6 eGMP compliance

7 Manufacture for sale

Form-25

8

Process flow chart

indicating different

sites involved in

manufacturing and

releasing

9

Certificate of GMP

compliance and

manufacturing

10 Manufacturer GMP

11

Qualified person

declaration

concerning GMP

compilace

12 Labelling documents

13 Patent information

leaflet

14 BE requirements

5. DISCUSSION

Generic Drug Registration And Requirements In All Valid European Union

There are four different registration procedures (marketing authorization procedures) for

generic drugs in all valid European union. There are two regulatory steps to go through

before a drug is approved to be marketed in the European Union. These two steps are clinical

trial application and marketing authorization application. The European Medicines Agency

(EMA) is responsible for the scientific evaluation of centralized marketing



authorization applications (MAA). Once granted by the European Commission, the

centralized marketing authorization is valid in all European Union (EU) Member States,

Iceland, Norway and Liechtenstein.

Procedures for application for a marketing authorization

Centralized procedure

National procedure

Mutual recognition procedure

Decentralized procedure

Centralized Procedure (CP)

Figure 4: Summary of Centralized Procedure.

National Procedure (NP)

Generally, this procedure is no longer used nowadays. If an applicant wishes to obtain a

license in one Member State (MS) an application must be made to the national Competent

Authority (CA) which then issues a national license. With the exception of products granted a

marketing authorization under the centralized procedure as set out above, all products are

granted marketing authorizations on a country-by-country basis by the competent authorities

in each Member State. Such marketing authorizations permit the holder to market the product



in question in the Member State concerned, subject to any restrictions or requirements that

accompany the authorization.

Mutual Recognition Procedure (MRP)

Figure 5: Summary of Mutual recognition procedure.

Decentralized procedure (DCP)

Figure 6: Summary of Decentralized procedure.



Table 9: Summary of European marketing application options.

Process When used Pros Cons

National

authorization

Individual application to each

country within the EU. Used for

products that fall outside the scope

of the EMA centralized procedure

If application rejected in

one country, can still

access other Europe

countries

Separate application

required for each

country. Unique

requirements and

formats may be

required

Decentralized

procedure

Used for products that fall outside

the scope of the EMA centralized

procedure.

Simultaneous

authorization in numerous

countries in the EU. May

be more efficient than

national authorization

since a positive outcome

results in numerous

country approvals.

Sponsors can select which

countries to apply to;does

not have to be all EU

countries

A negative decision

on an application may

affect numerous

countries.

Mutual

recognition

procedure

Individual application to one

country which in the EU for

products that fall outside the scope

of the EMA centralized procedure

Review by one country

and other countries accept

the decision. Only one

application needs to be

submitted.

Individual national

approvals can add

significant time to the

process. A negative

outcome can effect

numerous countries.

Centralized

procedure

Used for biological products or

other products using high

technology procedures; products

for HIV/AIDS, cancer, diabetes,

autoimmune or dysfunction, and

viral diseases, product for orphan

conditions;and other new active

substance at the request of the

applicant.

One application applies to

all countries in the EU.

Relatively quick

procedure. A positive

outcome is very

beneficial to the sponsor.

A negative outcome

will affect access to

the entire EU.

Procedures for obtaining a marketing authorization

Authorization processes follow either a purely national procedure, with rules and

requirements as per national legislation in force, as it occurs in most of countries worldwide,

or should follow a centrally approval or a mutual recognition or decentralized procedure

within the European Union.



Steps involved in obtaining an EU marketing authorization

Submission of eligibility request

Notification of intention to submit an application

Appointment of rapporteurs

Pre-submission meeting

Reconfirmation of communicated submission date

Submission and validation of application

Scientific evaluation

CHMP scientific opinion

European commission decision

Dossier to be submitted

The EMEA requires from the applicant: One full copy of the dossier (modules 1-5 according

to the EU-CTD format), including the applicant’s part of the Active Substance Master File, if

any; Two additional copies of Modules 1 and 2 including the draft summary of product

characteristics, labelling and package leaflet in English; One electronic copy of module 1

and 2 (at least 2.1-2.5) in WORD. In addition, applicants must submit the dossier to both the

Rapporteur and the Co-Rapporteur in parallel to the EMEA. Otherwise there may be a delay

in the start of the procedure because of the time lapse between the validation by the EMEA

and the confirmation from the Rapporteur and the Co-Rapporteur that they have received the

dossiers.

Validation by the EMA

During validation the EMA Product Team Lead (PTL) consults the Rapporteur and Co-

Rapporteur, on the need for action relating to matters such as GMP inspection, ad-hoc expert

groups, Scientific Advisory Groups, GCP inspections, and completeness of data.



Positive outcome of the validation

Negative outcome of the validation

Types of applications

The type of application may vary according to status of the active ingredient.

Thus, if the application concerns a new active ingredient (new active substance, new

chemical entity, new molecular entity), one talks about a full application.

Generic Application – According to Article 10 (I) of Directive 2001/83/EC, the applicant is

not required to provide the results of Pre clinical tests and Clinical tests if he can demonstrate

that the medicinal product is a generic medicinal product of a reference medicinal product

which is or has been authorized for not less than 8 years in a Member State or a Community.

A medicinal product is defined as a generic medicinal product if it has:

The same qualitative and quantitative composition in active substance as that of reference

product.

The same pharmaceutical form as the reference product.

And whose Bio-equivalence with the reference medicinal product has been demonstrated

with appropriate Bio-availability studies.

6. CONCLUSION

The primary purpose of the rules governing generic drugs in Europe is to safeguard to public

health. It is the role of public regulatory authorities to ensure that pharmaceutical companies

comply with regulations. There are legislations that require drugs to be developed, tested,

trailed, and manufactured in accordance to the guidelines so that they are safe and patient’s

well - being is protected. The regulatory submissions in the EU, in the world continue to have

significant differences. When compared to others the EU approval process is typical and

contain more data to be summarized for the dossier submission. All OECD countries see the

development of generic markets as a good opportunity to increase efficiency in

pharmaceutical spending but many do not fully exploit the potential of generics. Some of the

differences in generic uptake can be explained by market structures, notably the number of

off-patent medicines, and by prescribing practices, but generic uptake also very much

depends on policies implemented by countries. It also compares the registration procedure,

regulatory pathways for the registration of drugs in EU. The EU requires to select from any

one of the marketing authorization procedure.



To succeed with multinational registrations, a sponsor must:

Identify key target markets for submissions.

Understand important regional differences.

Find the right local resources to avoid regulatory pitfalls.

Create a robust CTD (Common Technical Document).

7. REFERENCE

1. European Commission. Guidance on elements required to support the significant clinical

benefit in comparison with existing therapies of a new therapeutic indication in order to

benefit from an extended (11 years) marketing protection period, 2007. Available

from: http://ec.europa.eu/health/files/eudralex/vol-2/c/guideline_14-11-2007_en.pdf

2. European Commission Competition, EU Sector inquiry, 8 July 2009. Available

from: http://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/communication_en

pdf

3. Tschabitscher D, Platzer P, Baumgärtel C, Müllner M. Generic drugs: quality, efficacy,

safety and interchangeability. Wien Klin Wochenschr, 2008; 120: 63-9.

4. American Medical Association. Summaries and recommendations of Council on

Scientific Affairs Reports. Generic drugs (CSA Rep 6, A-02). 2002 Annual Meeting of

the American Medical Association, 2002; 13-4.

5. Henney JE. Review of generic bioequivalence studies from the food and drug

administration. JAMA, 1999; 282: 1995.

6. G. Sai Hanuja, B. Sai Kumari, M.V. Nagabhushanam, D. Nagarjuna Reddy, Brahmaiah

Bonthagarala, Regulatory Requirements for Registration of Generic Drugs in “BRICS”

Countries, International Journal of Pharmaceutical Science and Health Care, ISSN 2249 –

5738, November-December 2016; 6(6): 20-40.

7. L Evangeline, NVN Mounica, V Sharmila Reddy, MV Ngabhushanam, D Nagarjuna

Reddy and Brahmaiah Bonthagarala, Regulatory process and ethics for clinical trials in

India (CDSCO)- A Review, The Pharma Innovation Journal, ISSN (E): 2277- 7695, ISSN

(P): 2349-8242, 2017; 6(4): 165-169.

8. B. Sai Kumari, G. Sai Hanuja, M.V. Nagabhushanam, D. Nagarjuna Reddy, Brahmaiah

Bonthagarala, Current Regulatory Requirements for Registration of Medicines,

Compilation and Submission of Dossier in Australian Therapeutic goods Administration,

International Journal of Advanced Scientific and Technical Research, ISSN 2249-9954,

November-December 2016; 6(6): 144-157.

http://ec.europa.eu/health/files/eudralex/vol-2/c/guideline_14-11-2007_en.pdf

http://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/communication_en.pdf

http://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/communication_en.pdf



9. Shaik Salman Basha, S. M. Shakeel, M. V. Nagabhushanam, D. Nagarjuna Reddy,

Brahmaiah Bonthagarala, The Assesment of Current Regulatory Guidelines for

Biosimilars- A Global Scenario, World Journal of Pharmaceutical Research, ISSN 2277–

7105; 6(1): 351-369.

10. S.M. Shakeel, Shaik Salman Basha, M.V. Nagabhushanam, D. Nagarjuna Reddy,

Brahmaiah Bonthagarala, Comparision of Regulataory Requirements for Generic Drugs

Dossier Submission in United States and Canada, International Journal of Pharmaceutical

Science and Health Care, ISSN 2249 – 5738, November-December 2016; 6(6): 1-19.

11. Srinivasan R. Indian pharmaceutical industry: Evaluation of current scenario and future

trends. [Last accessed on 2012 Jun 10]. Available from: http://www.tejas-

iimb.org/interviews/13.php.

http://www.tejas-iimb.org/interviews/13.php

http://www.tejas-iimb.org/interviews/13.php